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Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.

Life in the Drug Labs

Wastes of Time (And Not)

Couldn’t blog on the train this morning, and pushing back the frontiers of science has occupied me since then. And news is scarce, as it often seems to be in mid-August. So I’ll throw out a dual question to the readership, building on one that got started in the comments section the other day.

A. What was the biggest waste of time, in retrospect, that you’ve been part of in your scientific career?

B. What was the best thing that you thought would be a waste of time, but turned out to be valuable?

For my part, in the first category, I can think of a couple of projects from some years ago that were basically doomed pretty much from the start, so those are strong contenders. I did manage to salvage some interesting chemistry (and a few good stories) from them, though, so it’s hard to mark them down as total losses. The time certainly could have been better spent, however! In the grad-school answer division, I can’t say that the class time I spent learning about electron spin resonance has ever paid off very much, looking back on it.

As for the second category, I don’t think I’ve ever regretted learning any of the (modern) analytical techniques that I’ve picked up over the years, even if I wasn’t sure that I’d ever need to run them again. And like anyone else, I’ve pursued some unlikely-looking compound series, just to be complete about things, that turned out to be real, and really useful. But I’d have to say that another project outcompetes those: I didn’t intend for this blog to be a waste of time per se, but the original idea was just to have something to do in the evenings, just for the heck of it. I would not have been able to predict that I’d still be doing it (and enjoying it) in 2016, that’s for sure, so it’s definitely turned out to be much more than I’d thought.

40 comments on “Wastes of Time (And Not)”

I can think of many interviews for med. chem. roles over the years which turned out to be a huuuuge waste of time.

As for no. 2 I have a few thoughts: how many times have you ‘wasted time’ on a series that turned out to be fatally flawed, then get very annoyed with yourself for not spotting it, and subsequently found out that pretty much all of the SAR tracks into better series?

As for other things I thought would be a waste of time before I did them, and they turned out not to be, they tend to be lectures and conferences where I learned something valuable.

The first is pretty easy after nearly 30 years in Pharma. Management change initiatives that lack the real commitment to do something other than the status quo.

On the upside, everything I’ve learned in the data analysis/IT world. Data sets are only getting larger and more complex, so it’s more difficult to sort out the chaff from the grain. Also everything that I’ve done around “networking” from giving external talks or participating in professional societies. It’s been incredible the number of times those connections re-enter my life or help me personally or professionally.

The biggest waste of time I had was spending about 2 years trying to reinvent a macrocyclic ring synthesis because I was frustrated about lack of commercial availability / cost and because I thought the literature precedents for it were atrocious. Turned out nothing worked in regards to alleviating the difficulty of that synthesis. Lot of time and money effectively burned up by it with nothing to show for it.

Simultaneously – the dents in my skull made from banging my head against the wall over that project are with me today, in the form of analytical experience, experimental management and knowing when to start throwing out vials verus jamming them on the backlog.

I think most chemists would probably agree that their more dire projects, even the failed ones yielded a similar knowledge base. When you get pushed against a deadline all sorts of strange experiments become appealing and I think just running some of those conditions ended up being enlightening, even if the project didn’t move forward at all.

The biggest waste of time was when I was once science project lead for a project that I could see from Day One not going anywhere, but which I was “persuaded” (or else…) to spearhead. The project was scientifically interesting and challenging, but it did not fit in the company’s portfolio and direction, and it would have made more sense to sell it off. But because it came (in exchange for a significant payment) from the academic lab of an important consultant it was given project status. After a year and a half and a lot of hard work it was terminated when most of the R&D people at the particular site, myself included, were also terminated.

I recall a group of senior folk whose primary function was to be informed and packaging the information to inform these folk could be draining at times. Months later you’d get the feedback for your project. Packed with penetrating insight like ‘reduce logD’ because it correlates with promiscuity (and only 6 months after you packaged the project information in Reader’s Digest format).

It’s a little surprising to me how much A is emphasized and B is deemphasized.

I mean, OF COURSE the most important findings are going to be unexpected. That’s where our ideas either failed to predict reality correctly or did not even imagine the case in the first place. And it’s those kind of situations where we really stand to learn something.

Writing a chapters for a couple of conference books has been the biggest waste of time. Publication of such books is usually delayed by 1 or 2 years – yawn – and when you check back 10 years later at the number of citations it gets you, you become determined never to say YES again when you get an invitation to write another chapter.

A. Far too many. But an obsession from on high with implementing Lean Sigma into drug discovery comes high on the list. I watched with some level of detachment until I was made department head, when it became painfully and quickly obvious exactly how much time was being wasted on this crap, and how difficult it was to stop the train-wreck of a process and get on with something more useful. Experiments, for example. See also – IT projects with a life of their own, small molecule projects with a loud-mouth project leader and no pharmacology, etc, etc.

B. Bringing a talented facilitator into a dysfunctional management team, and also, taking the time myself to go on (some) leadership training, contrary to my own instincts. It is worth remembering that scientists often become managers because they are good (or at least, organisationally sucessful) scientists with ambition rather than leaders, and the transition can be difficult unless you are humble.

Agggghhhh! Lean Sigma. It just gave me the shakes to see that again. I’m with ya. That was the first pre-packaged, trendy management module that really underscored how far things were drifting away from sense and earned wisdom into corporatism. And then we merged with Glaxo…

Have not seen pushes for six or lean sigma in our research area for quite some time and it’s been a real relief. There seems less buy-in to guru-think and managerial fads these days. It’s almost as if science-based considerations are winning over voodoo, forcing things into dubious classification schemes and wrapping concepts with trendy lingo.

‘Win-win’, ‘fail faster’, ‘synergy’ and related, empty phrases have become much less common here.

Ted himself may well have more details, but in general, phosphatase inhibitors have been a wasteland for compound progression. It’s very hard to find hits for them that aren’t false positives of one sort or another, and when you do, the chemical matter tends to be very unattractive. Best guess is that the binding site, which wants a phosphate, is a poor fit for most small molecule compounds collections. You see something similar on the kinase side – tons of inhibitors, but very, very few that interact with the ATP binding site that recognizes all those phosphates.

Biggest waste of time: spending 1.5 years filling out a 20-substrate table with >90% yields and ee’s. Yeah, the paper made it into Nature, but the reaction was completely useless (100’s of substrates synthesized and screened to bad results, of course these were never mentioned). We pitched it as a, “general solution to a longstanding problem in synthesis,” but I’m pretty sure that all we did was get another lemon off the lot…

A: 9000 selective, chemokine antagonists which are well tolerated & don’t work because what you really want is a promiscuous chemokine antagonist….
B: learned lots of cool pharmacology & insights in drug R&D working on 9000 selective, chemokine antagonists…..

tHe biggest waste of time is having bad coworkers on your project who can easily tack on months to a project you can complete yourself. It’s not just the strain of training them (AND them not improving), but it is the time it takes to interpret their junk data in a proper theoretical framework and design/conduct the experiments to prove that their conclusions are erroneous. Oh, and then your boss reprimands you for questioning the white male patriarchy

A. Unfortunately has happened twice along the way in finding out too late was working for subtly deceitful managers, supposedly good scientists themselves who best skill was taking maximum credit for any idea/progress of others while deflecting the blame for set-backs from themselves, especially in fooling those above them.

B. Supervisor/Team Building sessions as even though have encountered a number as useless a couple did aid personal development and group comradeship (especially in understanding and applications of Myers-Briggs assessments)

Ha! I started the safety committee at a previous employer, or more accurately I caused it to start. I had noticed a number of safety issues, wrote up a one-page memo listing about a dozen of them, and gave it to the company lawyer. That sparked creation of the committee, but management didn’t want me to be on it.

But one of the committee members did want me on it, so as a substitute we toured the whole plant looking for problems. We found a lot more than were in my memo. There was one room where we were using fluorine in gas bottles, and there was a fluorine detector/alarm on the wall. It was connected to two sensors several feet apart, and I noticed the sensors had red plastic caps on them. These were protective caps used for shipping, and nobody had ever removed them. It had been in use for several years that way.

There was another room where carbon dioxide was being used. There was a monitor on the wall. The person I was with said “That’s a carbon dioxide monitor.” “Oh yeah?” I said. I took it off the wall, and it was a carbon monoxide monitor like you’d get at Home Depot. It still may have worked — I checked the datasheet on the carbon dioxide we were using, and it contained a significant amount of carbon monoxide. When the carbon dioxide was purged from the equipment we were using, it was vented into the room, so that was a safety issue.

We found lots of other issues. I think the total was something like a hundred issues. At my next employer (a much larger company), new employees had to go through a safety training course before doing anything. Most of the other attendees of that course thought it was a joke and waste of time. I didn’t. Those others didn’t know what really bad looks like.

a) working in an academic group, doing their instrumental analysis while waiting for some targetable pathway to be nailed down (I was young, foolish and needed a work visa when I took the job)

b) towards the end of that time the group was so low on money that they asked if I could get some other work through my contacts in other departments. That lead to me getting enough teaching experience to be taken on as faculty at another uni

A. Attending obligatory staff meetings in pharma, orchestrated by senior management, that involve pedestrian topics like: releasing innovation, releasing energy, compound quality, big data, performance ratings, site closures, reorganizations and lean efficiency. Insult to injury (lost time) can also occur if it becomes painfully obvious that management is just bull-s#%*ing their way through the meeting as they go through the motions of justifying their positions, oblivious to science, logistics, or their own pretense. Avoid such meetings like the plague. If you do get trapped in one, treat it is an opportunity to study social psychology or cult rituals – if kool-aid is offered, drink at your own risk. Time would be much better spent, and morale improved, by having a keg party instead.

B. You never know when someone might pipe-up at a project meeting, even a project on life support, with a key observation or suggestion that can turn things around. Project leaders and project teams need to be open to moments like that, especially if the status quo isn’t fruitful.

Not sure about the meetings. Yeah they’re a waste of time productivity-wise, but when the company has to do a re-org, attendance at meetings or even the level of ‘enthusiasm’ shown can sometimes make a difference between staying and being sent away. Cult rituals are there for a reason … to weed out the non-believers.

Of cos, whether one wants to stay in such an environment is another matter, but it’s always good to have more options.

My PhD supervisor believed that when the cost of performing a particular task becomes larger than the benefit derived from it, then performing that task should be abandoned. To put it as an example: if it takes X number of reactions to get your idea published in JACS, then my PhD supervisor would discourage us from running X+1 reactions (unless that additional reaction promoted the quality of our report to a better journal). My postdoctoral supervisor, on the other hand, did not share the same ideology – he published every report only when he felt the study was fully complete and no stone was left unturned. This to me, an individual early in his career trying to get publications under his belt, seemed like a waste of time. Our manuscript was ready for submission after 6 months of work, yet we wasted another 6 months trying to set up additional reactions that would “make the study more complete” even though those additional reactions did not promote our manuscript to a better journal. My proposal of saving and reassigning the additional work for a 2nd report to be published as a more thorough and exhaustive investigation of our currently raw and preliminary idea was also shot down by my postdoctoral advisor. I know there are many perfectionists in the chemical community and I’m sure they will take the side of my postdoctoral advisor… and that’s ok. I am just not one of them.

1. Typesetting the PhD thesis in LaTeX; running experiments with contaminated samples from other people blindly trusting that they are OK instead of checking; synthesis of 3.5 kDa ‘small molecules’ (at least that was fun); listening to career advice from the postdoctoral advisor.
2. Learning homology modeling and docking, starting from zero knowledge of the field. It turned out to be quite a fruitful endeavor (in terms of papers) despite my deep initial scepticism; writing a blog.

Only having done a Ph D and then having hightailed it out of research as fast as I could:

(1) Synthesizing molecules I was set on which fell apart in water, so they clearly could not be added to cells, the stated purpose of the project. There was literature that was at least 20 years old which would have told “us” this had someone done a scifinder search before I spent a year making the compounds.
(2) Attempting a synthesis my supervisor suggested was a waste of time. The group meeting that week went: “Here is an NMR of the ligand that can’t be made, and here is an NMR of the complex of that ligand, and here is its crystal structure”. Good times.
The response: “Yep, that was a bad idea. Now we know it works, you should make all of these ligands too.”

A) Two projects in different groups, which certain people in the group knew wouldn’t work or were pointless duplication of something someone else was doing. But no one said anything in group meeting.

B) Working for a year with the wrong material sent by a collaborator. When we did the detective work to decipher what they sent us, all the seemingly interesting results became very dull. But I did some of my most comprehensively rigorous work to show that they’d made the mistake, and picked up plenty of skills along the way. Shame that report will never see the light of day….

A: All those crap antibacterial projects against essential genes (that weren’t essential) that I worked on with a crap compound collection. The Christmas tree compound that came up in every screen! (But I learned a ton of biology, understood how assays worked (or not) and got a handle on what good compounds looked like. Great, insightful bosses helped a lot. I learned that the starting point of a project, whether it be the biology or the chemistry is 90% of the game.)

B: Learning how patents, contracts and the finances of pharma worked. Seemed like I was selling my soul, but turned out to give me a second career that I never expected and prevented me from being out of work for too long once it became obvious nobody wanted to employ chemists.

A) The collection of efforts to make R&D more efficient: Six sigma, fail fast, xyz change initiatives, re-orgs to TAs, to Franchises, to any new structure that will magically impose efficiency.
a) Training the new ‘leadership’ from academia that was valued over internal drug discovery experts because of reputation in the field, and the related experience of proving experts data wrong.

B) Management training that seems stupid and simple and frustrating but that givers me tools I use for years and years,

A. Trying to combine activity at a neurokinin receptor (really hard in itself, does very little in vivo) with activity at other targets in a dual pharmacology in one molecule kind of way.
Pretty much any project trying to find a back up to the lead candidate.
Any work done in the years leading up to a site closure.

B. Writing papers. Should have written more papers. Giving talks. Running workshops.